(Circulation. 2000;102:565.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Adenovirus-Mediated VEGF121 Gene Transfer Stimulates Angiogenesis in Normoperfused Skeletal Muscle and Preserves Tissue Perfusion After Induction of Ischemia
Presented in part at the 48th Annual Scientific Session of the American College of Cardiology, New Orleans, La, March 8, 1999, and published previously in abstract form (J Am Coll Cardiol. 1999;33(suppl A):250A.
From the Gene Therapy Unit, Laboratory of Cardiovascular Science (L.H.W.G., L.P., X.W., E.G.L., M.T.) and Nuclear Magnetic Resonance Unit, Laboratory of Cellular and Molecular Biology (K.W.F., R.G.S.S.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Md; GenVec Inc, Rockville, Md (I.K.); Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (A.Z., R.P., S.S., C.E., M.M.-T., M.C.C.); and Department of Medicine, New York Medical College, Valhalla (P.A.). Drs Spencer, Talan, and Capogrossi contributed equally to this article.
Correspondence to Mark Talan, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail talanm{at}grc.nia.nih.gov
Background—Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF121) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia.
Methods and Results—Rabbits and rats received IM injections of AdCMV.VEGF121, AdCMV.Null, or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF121, we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF121 group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF121=5.69±0.40, AdCMV.Null=2.97±0.50, and saline=2.78±0.43 mL · min-1 · 100 g-1, P<0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF121=50.58±1.48, AdCMV.Null=29.08±4.22, saline=11.83±1.90, P<0.0001), and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by 31P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF121 group persisted until it was equalized by spontaneous collateral vessel development in untreated animals.
Conclusions—IM administration of AdCMV.VEGF121 stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.
Key Words: angiogenesis • endothelium-derived factors • genes • ischemia • peripheral vascular disease
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